FDA Struggles with Risk Management and Drug Safety

Intense public scrutiny of drug-safety issues is prompting the US Food and Drug Administration to take a closer look at its program for establishing Risk Evaluation and Mitigation Strategies (REMS) for new and existing medicines. The most restrictive REMS programs—those that include Elements to Assure Safe Use (ETASU)—are intended to apply only to high-risk products that cannot come to market without special safety controls. Healthcare providers and drug manufacturers, however, feel that the entire REMS program is overused, thereby raising costs and interfering with patient treatment.

REMS are at the center of many drug-safety cases and market-approval discussions. After a highly publicized review of the risks associated with GlaxoSmithKline's (GSK, London) diabetes treatment Avandia (rosoglitazone), advisory committee members voted to keep the drug on the market provided that FDA impose strict controls on prescribing through a restrictive REMS. Recent scrutiny of new antiobesity therapies indicates that manufacturers of these drugs will need to present fairly extensive REMS plans in order to enter the market. And the ongoing debate over devising a classwide REMS for long-acting opioids reflects the difficulties in imposing added safeguards on therapies that are in high demand but associated with dangerous abuse.

Although manufacturers are willing to implement these costly and sometimes cumbersome programs to meet FDA postmarketing safety requirements, doctors, pharmacists, and other healthcare providers are alarmed by the proliferation of new requirements for drug prescribing and dispensing. Health providers regard the new educational and patient-registration programs as a significant burden on their operations and on the healthcare system. Payers similarly are concerned about added costs, while consumers are caught between their desire for access to treatment and the need to avoid adverse events.

Recent advisory committees convened to evaluate proposed new drugs have debated these issues, as did participants at a two-day FDA public meeting in July on the REMS program. The shape and scope of REMS requirements have become central topics in discussions about revising the Prescription Drug User Fee program (PDUFA). Pharmaceutical companies and health professionals have begun to build the case for reform, with an eye on the user-fee renewal legislation slated for enactment by 2012.

Too many REMS

At the July public meeting, Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), acknowledged that the REMS program established by the FDA Amendments Act of 2007 (FDAAA) "is not perfect" and that FDA is looking for input from all stakeholders on "how we might remodel our house." FDA also published a draft guidance in October 2009 on what information manufacturers should include in REMS proposals and is reviewing comments on that document.

Everyone at the meeting acknowledged the importance of REMS in ensuring safe drug use. They also highlighted the unintended consequences of added postmarketing requirements at both ends of the REMS spectrum: more diverse Medication Guides as well as a growing number of highly restricted REMS with ETASU. The general complaint is that too many types of REMS exist and that FDA has not justified the need for special risk-management requirements. To date, the agency has approved more than 120 REMS, including 15 with ETASU, a number that Woodcock acknowledged has led to a proliferation of restrictions and requirements.

Pharmacists, physicians, and healthcare leaders outlined a host of burdens and costs imposed by multiple REMS and the paperwork involved in documenting compliance. Physicians complained of what they saw as redundant and unnecessary educational and training programs and policies that don't make sense. Why do providers have to enroll male patients in the iPledge program for isotretinoin which is designed to prevent pregnancy? asked Kaiser Permanente pharmacist Richard Wagner. Oncologists have been particularly vocal in opposing added educational requirements, noting that they are well trained to use chemotherapies that can be highly toxic. Pharmacists described how training, compliance tracking, and patient counseling takes time and interferes with pharmacy operations.

The most objectionable REMS feature for pharmacists and providers is the limited distribution systems for high-risk drugs. These requirements permit prescribing only by certain well-informed specialists and dispensing by designated specialty pharmacies that can verify appropriate use and patient understanding of the risks. Retail pharmacists complain that such systems steer patients away from regular pharmacies, while hospitals and health plans cite added costs and difficulties in obtaining therapies from restricted sources.